Model-Informed Translation of In Vitro Effects of Short-, Prolonged- and Continuous-Infusion Meropenem against Pseudomonas aeruginosa to Clinical Settings

Abstract

Pharmacokinetic-pharmacodynamic (PKPD) models have met increasing interest as tools to identify potential efficacious antibiotic dosing regimens in vitro and in vivo. We sought to investigate the impact of diversely shaped clinical pharmacokinetic profiles of meropenem on the growth/killing patterns of Pseudomonas aeruginosa (ARU552, MIC = 16 mg/L) over time using a semi-mechanistic PKPD model and a PK/PD index-based approach. Bacterial growth/killing were driven by the PK profiles of six patient populations (infected adults, burns, critically ill, neurosurgery, obese patients) given varied pathogen features (e.g. EC50, growth rate, inoculum), patient characteristics (e.g. creatinine clearance), and ten dosing regimens (including two dose levels and 0.5-h, 3-h and continuous-infusion regimens). Conclusions regarding the most favourable dosing regimen depended on the assessment of (i) the total bacterial load or fT>MIC (time that unbound concentrations exceed the minimum inhibitory concentration); (ii) the median or P0.95 profile of the population; and (iii) 8 h or 24 h time points. Continuous infusion plus loading dose as well as 3-h infusions (3-h infusions: e.g. for scenarios associated with low meropenem concentrations, P0.95 profiles, and MIC ≥ 16 mg/L) appeared superior to standard 0.5-h infusions at 24 h. The developed platform can serve to identify promising strategies of efficacious dosing for clinical trials.

Elucidating effects of single and multiple resistance mechanisms on bacterial response to meropenem by quantitative and systems pharmacology modeling and population genomics

“…Free (non-protein bound) meropenem concentration-time profiles were simulated in silico using Berkeley Madonna (v8.3.18), based on published population PK studies in critically ill patients with normal renal function (CLCR 120mL/min, meropenem t1/2 1.5h) (34,35), using clinically-relevant regimens (and associated modes of administration) as summarized in Table 2. Regimens were 1g and 2g as 3-h infusions given 8-hourly (Q8h), and 3g/day, 6g/day and 12g/day as continuous infusions (CI) (19,(36)(37)(38). Untreated controls were included for each strain.…”